3-Phenyl-propionaldehydes

ABSTRACT

There is disclosed a novel process for preparing a number of cinnamaldehyde derivatives. These cinnamaldehyde derivatives can be reduced to dihydrocinnamaldehyde derivatives, a number of which are commercially important in the preparation of fragrances. The invention is also directed to a number of novel intermediates and their preparation.

This is a division of application Ser. No. 06/322,135 filed Nov. 17,1981 and now U.S. Pat. No. 4,435,585.

BACKGROUND OF THE INVENTION

A number of substituted dihydrocinnamaldehydes are known odoriferoussubstances. W. Berends and L. M. v.d. Linde, Perfumery and Essential OilRecord, 58, 372 (1967). Some of these compounds, particularlyp-isopropyl-α-methyldihydrocinnamaldehyde andp-t-butyl-α-methyldihydrocinnamaldehyde, are among the principalaromatic compounds used in the industry.

These compounds are usually made by the multistep process shown belowwhich involves a condensation reaction of an aromatic aldehyde with theα-methylene of an aliphatic aldehyde ##STR1##

Other methods of synthesis are reviewed in the Berends article above. (Rand R' are suitable substituents provided to illustrate the generalutility of the prior art processes).

The success of this multistep process necessarily depends on theavailability of the appropriate corresponding benzaldehyde and theability to minimize side reactions such as self condensation of thealiphatic aldehyde and/or the Cannizzaro reaction.

More recently, U.S. Pat. No. 4,182,730 described a method for convertingan aryl alkyl ketone to the desired α-alkyldihydrocinnamaldehydes in aprocess which involves the Vilsmeier reaction as illustrated below.##STR2##

Nothing in the prior art discloses or suggests the novel process andintermediates disclosed herein.

THE INVENTION

This invention is concerned with a novel process for preparingcinnamaldehyde derivatives which can be illustrated as follows: ##STR3##wherein: R¹ represents isopropyl, n-butyl, sec. butyl, isobutyl,tert-butyl, methoxy or, together with R², represents methylene dioxy;

R² represents hydrogen, or together with R¹, represents methylene dioxy;

R³ represents hydrogen or methyl; and

R⁴ represents methyl or ethyl.

The cinnamaldehyde derivatives can then be hydrogenated by known methodsto the corresponding dihydrocinnamaldehydes as illustrated below:##STR4##

A number of compounds of formula IV are known odorant substances, e.g.

3-(p-isopropylphenyl)-2-methyl-propionaldehyde

3-(p-tert. butylphenyl)-2-methyl-propionaldehyde

3-(3,4-methyleneioxyphenyl)-2-methyl-propionaldehyde

3(p-methoxyphenyl)-2-methyl-propionaldehyde

3-(p-tert.butylphenyl)-propionaldehyde

3-(p-n-butylphenyl)-2-methyl-propionaldehyde,

3-(p-isobutylphenyl)-2-methyl-propionaldehyde and

3-[p-(α-methylpropyl)-phenyl]-2-methyl-propionaldehyde.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The first step of the novel sequence (step a) involves converting theketone of formula I to the novel ketal of formula II. The conversion ofthe ketone to the ketal can be carried out by methods similar to thoseknown in the art, for example, by treating a compound of formula VI withethanol or methanol and ethyl orthoformate or methyl orthoformate in thepresence of catalytic amounts of p-toluenesulphonic acid. Theketalization is conveniently carried out at room temperature or aslightly higher temperature (e.g. 30°-80° C.).

The novel ketal of formula II can be converted to the enol ether III byan acid-catalyzed elimination of the alcohol R⁴ OH, the alcohol beingdistilled off as it is formed.

The distillation can be conveniently carried out, e.g in the case ofethanol, at temperatures of 110° to 170° C. with 130° C. to 150° C.being preferred.

When methanol is eliminated, comparable results may be obtained atsomewhat lower temperatures.

A key step in the process is step c which involves the hydroformylationof the enol ether III to form a novel β-alkoxy aldehyde of formula IVwhich can, in turn, be converted to the cinnamaldehyde derivative V byalcohol cleavage, for example acid catalysed alcohol cleavage.

The hydroformylation, in accordance with the invention, can be carriedout using carbon monoxide and hydrogen, conveniently in the volume ratioof 1:4 to 4:1 with a volume ratio of 1:3 to 3:1 being preferred. It isadvantageous to use this gas mixture in excess based on the startingenol ether of formula III (e.g. up to a 20-100 fold molar amount).

The hydroformylation is preferably carried out at temperatures of 50° to150° C. Temperatures of 90° to 120° C. have proved to be especiallypreferred.

The hydroformylation is conveniently carried out under pressures of 150to 700 atmospheres, with pressures of 250 to 500 atmospheres beingpreferred.

The hydroformylation is preferably carried out in the presence ofrhodium catalysts. Examples of catalysts which are preferred are thepure metal, oxides, salts or complexes, for example

Rh/C (e.g. 5%),

RhCl₃.H₂ O

Rh₂ O₃,

Rh(PPh₃)₃ Cl,

RhHCO(PPh₃)₃,

RhCO(PPh₃)₂ Cl and

Rh₆ (CO)₁₆.

From this compilation, it is evident that the catalysis can be carriedout not only in a homogeneous phase but also in a heterogeneous phase.It is preferred to carry out the catalysis in a heterogeneous phase. Itis preferred to use 0.01 to 0.5 wt.% rhodium (calculated as the metal)based on the enol ether of formula III with amounts of 0.03 to 0.1 wt.%of rhodium being especially preferred.

The process provided by the invention is carried out, for example, byproviding the ether of formula III, optionally together with solvents,introducing the rhodium catalyst in the indicated amounts (e.g. in apressure autoclave) and, while feeding in the mixture of carbon monoxideand hydrogen in the indicated ratios, carrying out the hydroformylationunder the aforementioned temperature and pressure conditions. Thehydroformylation can, however, also advantageously be carried outcontinuously in a suitable apparatus. After cooling, the product isde-pressurized and the excess mixture of carbon monoxide and hydrogen isseparated and, if desired, used again, while the liquid product isworked-up according to usual methods (e.g. by distillation), whereby theβ-alkoxy aldehyde of formula IV is obtained as the main product. It isnormally not necessary to isolate this product in pure form. For thefurther processing, it is sufficient merely to separate the catalyst asa sludge in a first distillation and to further process the crudemixture.

The β-alkoxy-aldehydes of formula IV, which are novel and also form anobject of the invention, can be converted by alcohol cleavage (e.g.acid-catalysed alcohol cleavage) into the cinnamic acid derivatives offormula V as shown in step d.

This alcohol cleavage is conveniently carried out under acid conditions,with mineral acids such as hydrochloric acid or sulfuric acid beingespecially suitable, and at temperatures between 20° and 100° C., ifdesired in the presence of an inert solvent (e.g. toluene).

The cinnamaldehyde derivative of formula V may be converted to thedihydrocinnamaldehyde derivatives of formula VI (step e) byhydrogenation according to methods known in the art, e.g. using a Pd/Ccatalyst. See P. Bedoukian, Perfumery & Flavouring Synthetics, Elsevier,Amsterdam, London, New York 1967, 151 or U.S. Pat. No. 2,875,131. Thefollowing examples are offered to illustrate the present invention.

EXAMPLE 1

(a) 1.050 liters of 1,2-dichloroethane are placed in a 21/2 litersulphonation flask and thereupon 418 g of aluminium chloride areintroduced. The mixture is cooled to 0° C. and, within 13/4 hours, 254 gof propionic acid chloride are added dropwise thereto at 0°-5° C.(ice/acetone cooling). The mixture is left to warm to 18° within 30minutes and now there are added dropwise thereto 350 g oftert.butylbenzene at 20° within 2 hours. In so doing the mixture iscooled slightly with water. The mixture is stirred for 2 hours and leftto stand for 12 hours. Thereafter, the mixture is poured while stirringinto a mixture of 1.600 kg of ice, 260 ml of water and 260 ml ofconcentrated hydrochloric acid, the temperature always being held below20° C. The aqueous phase is separated and extracted with two 500 mlportions of dichloroethane. The combined organic phases are washed (pH6) once with 1 liter of water, three times with 400 ml of 2% sodiumhydroxide and once with 500 ml of water. The solvent is removed on arotary evaporator and the residue (505 g) is distilled in vacuo over a50 cm column.

B.p./0.01 mmHg-100° 50 g: First runnings; -102° 425 g:p-Tert.butyl-propiohenone, n_(D) ²⁰ =1.5164; Residue 20 g.

Boiling point of the pure compound: 92°-94° C./0.04 mmHg n_(d) ²⁰ :1.5184; IR: bands inter alia at 1685 and 1605⁻¹ and 800, 950 and 1225cm⁻¹.

(b) 296 g of absolute alcohol and 6.5 g of p-toluenesulphonic acid areplaced in a 41/2 liter sulphonation flask. 1233 g ofp-tert.butyl-propiophenone are added dropwise within 30 minutes. Now,953 g of triethyl orthoformate are added thereto. The temperature isheld at 30° by cooling with water. The mixture is subsequently stirredat 20°-25° for a further 22 hours. The mixture is adjusted to pH 8 with31 ml of triethylamine and poured while stirring into 300 ml of 5%bicarbonate solution and 500 g of ice. The aqueous phase is extractedonce with ether and the organic phase is washed with 5% bicarbonatesolution. After adding 1 g of soda, the solution is concentrated on arotary evaporator. In order to remove the water as completely aspossible, 500 ml of methylene chloride are subsequently added and themixture is evaporated once more. The residue is distilled in vacuo overa 15 cm Vigreux column with the addition of 1 g of soda.

B.p. 0.05 mm-92° 27 g: First runnings; ˜92° 1600 g:p-Tert.butyl-propiophenone diethyl ketal; n_(D) ²⁰ =1.4821 (94.1%);Residue 15 g.

Boiling point of the pure compound: 102°/0.2 mmHg; n_(D) ²⁰ =1.4830; IR:bands inter alia at 835, 975, 1050, 1090, 1120 and 1170 cm⁻¹.

In the distillation some enol ether is already obtained from the ethylketal.

(c) 500 g of p-tert.butyl-propiophenone diethyl ketal and 6 g ofp-toluenesulphonic acid are heated (oil bath, 140°) in a distillationapparatus fitted with a 15 cm Vigreux column. The alcohol formed isdistilled off continuously. 100 ml of alcohol can be distilled offwithin 3 hours. The mixture is now evaporated under a water-jet vacuumand the residue is subsequently distilled in a high vacuum.

B.p. 0.05 mmHg-90° 10 g: First runnings; 91° 352 g:p-Tert.butyl-propiophenone enol ethyl ether, n_(D) ²⁰ =1.5160 (85.2%);Residue: 55 g (polymerised).

Boiling point of pure compound: 93°/0.01 mmHg; n_(D) ²⁰ =1.5153; IR:bands inter alia at 850 and 1070 cm⁻¹.

(d) A solution of 0.135 g (0.127 mmol) of Rh₆ (CO)₁₆ and 109 g (416mmol) of 83.3% of the above enol ether in 100 ml of benzene is chargedunder argon into a 500 ml Uhde stirring autoclave evacuated four timesto 1 mbar and in each case gasified with argon. The autoclave ispressurized to 240 bar with carbon monoxide and hydrogen in the ratio of3:1. The mixture is heated to 90° C. while stirring. The pressureincreases to 290 bar upon heating.

The course of the hydroformylation is followed by gas chromatography.After completion of the hydroformylation the mixture is cooled to roomtemperature. The mixture is rinsed from the autoclave and evaporated ina rotary evaporator at 60° C. and under a water-jet vacuum. The brownoily product (119.7 g) is gently distilled (1 mbar, 125° C. bathtemperature) in order to separate the catalyst and gives 100.2 g ofhydroformylation product as a yellow oil which, in accordance withanalysis by gas chromatography, consists of 62.1% of the 2-formylcompound, namely 1-(p-tert.butylphenyl)-1-ethoxy-2-formyl-propane. Inaddition, a small amount of the corresponding 1-formyl compound, namely1-(p-tert.butylphenyl)-1-ethoxy-1-formyl-propane, is obtained. This factcan be proved by the IR-spectrum and NMR-spectrum.

(e) 100.2 g of distilled hydroformylation mixture are stirred with 2 ml(15.4 mmol) of concentrated hydrochloric acid for 6 hours at 50° C. Assoon as the entire 2-formyl compound of formula I has reacted (as shownby the analysis of a sample by gas chromatography), the resulting ethylalcohol is removed by evaporation in a rotary evaporator at 60° C. andunder a water-jet vacuum and the mixture (91.4 g) is neutralized withthe addition of 1.5 g (90 mmol) of pyridine and distilled over a 25 cmVigreux column with a vacuum mantle in a high vacuum (0.07 mbar). At aboiling range of 75°-80° there are obtained 41.7 g of1-(p-tert.butylphenyl)-2-formyl-1-propene. M.p. (from hexane) 68°-70° C.

(f) 1420 g of 1-(p-tert.butylphenyl)-2-formyl-1-propene, prepared asdescribed in paragraph (e), are mixed together with 6 g of 5%palladium/carbon and 6.8 g of soda in 20 ml of water at 70°-75° C. in astirring autoclave. The autoclave is charged with hydrogen (8atmospheres) and heated to 110° C. About 230 liters of hydrogen areabsorbed after 12 hours. The crude3-(p-tert.butyl-phenyl)-2-methyl-propionaldehyde is treated with ether,washed neutral with water and dried over sodium sulphate. After removingthe ether, the product is fractionally distilled in vacuo. Afterseparating a first running and a last running, there are obtained 1275 gof 3-(p-tert.butyl-phenyl)-2-methyl-propionaldehyde in 95% purity (about88% of theory). Boiling point: 150°-152° C./15 mmHg; n_(D) ²⁰ =1.5050.

EXAMPLE 2 (a) p-Isopropyl-propiophenone

525 ml of 1,2-dichloroethane and 209 g of aluminium chloride are addedto a round flask, which is fitted with a stirrer, thermometer, condenserand dropping funnel. The mixture is cooled to 0° C., and 127 g ofpropionic acid chloride are allowed to drop in at 0°-5° C. within 3/4hour. After the addition, the temperature is allowed to rise to +18° C.and then 157 g of cumene are added within 2 hours at 30° C. The mixtureis left to stand for 12 hours and the product is then poured into amixture of 800 g of ice, 130 ml of water and 130 ml of concentratedhydrochloric acid. The aqueous phase is separated and extracted with two250 ml portions of dichloroethane. The combined organic phases arewashed with three 200 ml portions of 2% sodium hydroxide and with 250 mlof water. The solvent is removed by evaporation under a vacuum and theresidue (244 g) is distilled over a 10 cm column. There are obtained192.1 g of p-isopropyl-propiophenone (yield: 83.2% of theory).B.p.=76°-77° C./0.15 mmHg; n_(D) ²⁰ =1.5150; d₄ ²⁰ =0.9645.

(b) p-Isopropyl-propiophenone diethyl ketal

48 ml of absolute ethanol and 1 g of p-toluenesulphonic acid are placedin a round flask which is fitted with a stirrer, thermometer, condenserand dropping funnel. Now, there are added dropwise within 30 minuteswhile stirring 181.5 g of p-isopropyl-propiophenone and subsequentlywithin 1 hour 152.5 g of triethyl orthoformate. The temperature is heldat 30° C. by external cooling. The mixture is subsequently stirred for afurther 22 hours at 20°-25° C. The mixture is then adjusted to pH 8 with5 g of triethylamine and thereupon poured into 50 ml of 5% bicarbonatesolution and 80 g of ice. The aqueous phase is separated and extractedwith ether. The combined organic phases are washed with 5% bicarbonatesolution and, after the addition of 0.3 g of sodium carbonate, thesolvent is removed by evaporation under a vacuum and the residue isdistilled over a 15 cm column. There are obtained 193.6 g ofp-isopropyl-propiophenone diethyl ketal (yield: 75.1% of theory).B.p.=66° C./0.05 mmHg; n_(D) ²⁰ =1,4778; d₄ ²⁰ =0,9305.

(c) 1-p-Isopropylphenyl-1-ethoxy-1-propene

150 g of p-isopropyl-propiophenone diethyl ketal are treated with 1.5 gof p-toluenesulphonic acid and heated in a distillation apparatus to140° C. (oil bath temperature). The alcohol formed is distilled offcontinuously at atmospheric pressure. 20 g of ethanol are distilled offwithin 3 hours. Now, the mixture is evaporated further under a water-jetvacuum and subsequently distilled in a high vacuum over a 30 cm column.There are obtained 50.6 g of 1-(p-isopropylphenyl)-1-ethoxy-1-propene(yield: 41.4%). B.p.=71°-72° C./0.1 mmHg; n_(D) ²⁰ =1.5093; d₄ ²⁰=0.9324.

The hydroformylation of the enol ether is carried out at 100° C., butotherwise in the same manner as described in Example 1. The same is alsotrue for the subsequent steps in which the conditions described inExample 1 can likewise be used. The yields are analogous to those ofExample 1.

EXAMPLE 3 (a) p-Methoxy-propiophenone

525 ml of 1,2-dichloroethane and 209 g of aluminium chloride are addedto a round flask which is fitted with a stirrer, thermometer, condenserand dropping funnel. The mixture is cooled to 0° C. and 127 g ofpropionic acid chloride are allowed to drop in at 0°-5° C. within 75minutes. After the addition, the temperature is allowed to rise to 18°C. and then 141.6 g of anisole are added within 2 hours and at 20° C.The mixture is left to stand for 12 hours and then the product is pouredinto a mixture of 800 g of ice, 130 ml of water and 130 ml ofconcentrated hydrochloric acid. The aqueous phase is separated andextracted with two 250 ml portions of 1,2-dichloroethane. The combinedorganic phases are washed with three 200 ml portions of 2% sodiumhydroxide and with 250 ml of water. The solvent is removed byevaporation under a vacuum and the residue (198 g) is distilled over a25 cm column. There are obtained 142 g of p-methoxy-propiophenone(yield: 66.4% of theory). B.p.=90° C./0.4 mmHg; melting point 26° C.;n_(D) ²⁰ =1.5451; d₄ ²⁰ =0.9645.

(b) p-Methoxy-propiophenone diethyl ketal

40 ml of absolute ethanol and 0.75 g of p-toluenesulphonic acid areplaced in a round flask which is fitted with a stirrer, thermometer,condenser and dropping funnel. Now, there are added dropwise within 15minutes while stirring 120 g of p-methoxy-propiophenone and subsequentlywithin 1 hour 108 g of triethyl orthoformate. The temperature is heldbelow 3° C. The mixture is subsequently stirred for a further 22 hoursat room temperature. The mixture is adjusted to pH 8 with 3.6 g oftriethylamine and then poured into 40 ml of 5% bicarbonate solution and60 g of ice. The aqueous phase is separated and extracted with ether.The combined organic phases are washed with 5% bicarbonate solution and,after the addition of 0.2 g of sodium carbonate, the solvent is removedby evaporation under a vacuum and the residue is distilled over a 15 cmcolumn. There are obtained 36.7 g of p-methoxy-propiophenone diethylketal (yield: 21% of theory). B.p.= 83°-84° C./0.4 mmHg; n_(D) ²⁰=1.4858; d₄ ²⁰ =0.9988.

(c) 1-(p-Methoxyphenyl)-1-ethoxy-1-propene

103.3 g of p-methoxy-propiophenone diethyl ketal are treated with 1.1 gof p-toluenesulphonic acid and heated in a distillation apparatus to140° C. (oil bath temperature). In so doing, the ethanol formed isdistilled off continuously at atmospheric pressure. 20 g of ethanol aredistilled off within 31/2 hours. Subsequently, the mixture remaining isdistilled in a high vacuum over a 15 cm column. There are obtained 62.2g of 1-(p-methoxyphenyl)-1-ethoxy-1-propene (yield: 74.8% of theory).B.p.=78°-79° C. 0.3 mmHg; n_(D) ²⁰ =1.5315: d₄ ²⁰ =1.0175.

The hydroformylation is carried out at 130° C., but otherwise in thesame manner as described in Example 1. The same is true for thesubsequent steps. The yields are analogous.

We claim:
 1. A compound of the formula ##STR5## wherein: R¹ representsisopropyl, n-butyl, sec.butyl, isobutyl, tert.butyl, methoxy or,together with R², represents methylene dioxyR² represents hydrogen or,together with R¹, represents methylene dioxy; R³ represents hydrogen ormethyl; and R⁴ represents methyl or ethyl.
 2. A compound of claim1wherein R¹ is isopropyl, tertiary butyl, or methoxy; R² is hydrogen;and R³ is methyl.
 3. A compound of claim 2wherein R¹ is tertiary butyl,and R⁴ is ethyl.